AB0144 PHARMACOLOGICAL CHARACTERIZATION OF GLPG3667, A SELECTIVE TYK2 INHIBITOR, SUPPORTS DEVELOPMENT IN DERMATOMYOSITIS AND SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: R. Aggarwal, E. F. Morand, R. Blanque, K. Shoji, M. Jans, F. Marsais, L. Furio, M. Colli, S. Lavazais, C. Cottereaux, C. David, N. Houvenaghel, I. Parent, E. Lagoutte, A. Van de Water, L. Perret, S. Alves, D. Amantini, S. Van der Plas, R. Galien
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Tyrosine kinase 2 (TYK2) is an intracellular kinase that transduces signalling from type 1 interferons (IFN), interleukin (IL)-12/ IL-23 and the IL-10 family of cytokines. Genetic analyses show an association of TYK2 variants with risk of inflammatory and autoimmune diseases. In addition, clinical data obtained with deucravacitinib (a TYK2 selective inhibitor) in SLE patients suggest that inhibition of TYK2 could be beneficial to patients with diseases driven by type I IFN such as systemic lupus erythematosus (SLE) and dermatomyositis (DM). <h3>Objectives</h3> We describe here GLPG3667, a TYK2 inhibitor in development for treatment of DM and SLE. <h3>Methods</h3> Potency and selectivity of GLPG3667 on TYK2 was assessed using radioactive, luminescent and fluorescent biochemical assays. Peripheral blood mononuclear cells (PBMC) and human whole blood assays for various Janus kinases (JAK)-dependent pathways were performed to assess GLPG3667 potency and selectivity, using flow cytometry or ELISA. GLPG3667 pharmacological activity was investigated in a psoriasis mouse model driven by IL-23. In healthy human volunteers (NCT04097938), pharmacodynamic activity of GLPG3667 was evaluated by measuring signal transducer and activator of transcription (STAT) phosphorylation using flow cytometry. Selectivity was assessed by analysing the impact of GLPG3667 on IFNα, IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) pathways. Biological effects of orally administered GLPG3667 in humans were assessed using transcriptomic analysis of blood cells after in vivo IFNα (1 million IU of Intron-A) challenge in healthy volunteers. <h3>Results</h3> Biochemical assays showed that GLPG3667 displayed a nanomolar potency on TYK2 with a &gt;3-fold selectivity over the other JAK kinases. In human PBMC activated with phorbol m12-myristate 13-acetate and ionomycin calcium salt, GLPG3667 showed comparable potency (around 50 nM) on the IFNα and IL-23 pathways. Potency of GLPG3667 was &gt;14-fold and &gt;19-fold higher in the IFNα pathway vs the IL-2 and GMCSF pathways in human PBMC and whole blood, respectively. In mice, dermal ear inflammation driven by IL-23 was prevented by GLPG3667 with a minimal effective dose of 3 mg/kg given orally once daily. This effect was associated with a decrease in neutrophil infiltration and STAT3 phosphorylation at sites of inflammation. In human healthy volunteers, GLPG3667 completely inhibited IFNα-induced STAT1 and STAT3 phosphorylation but did not impact IL-2- or GM-CSF-induced STAT5 phosphorylation. GLPG3667 strongly inhibited the expression of IFN-response genes induced by in vivo IFNα challenge in healthy human subjects. <h3>Conclusion</h3> GLPG3667 demonstrated selectivity for TYK2 relative to the three other JAK family members in biochemical and cellular assays, and in human whole blood assays ex vivo and in vivo during a phase 1 study in healthy human volunteers. Pharmacological effects of GLPG3667 were demonstrated in a mouse model of psoriasis driven by IL-23 and in human healthy volunteers challenged with IFNα. These data support the development of GLPG3667 in autoimmune diseases driven by type I IFN such as DM and SLE. <h3>Acknowledgements</h3> These studies were funded by Galapagos NV (Mechelen, Belgium). Editorial and publications management support was provided by PharmaGenesis London, London, UK and funded by Galapagos NV (Mechelen, Belgium). Publications coordination was provided by John Gonzalez, PhD, of Galapagos NV (Mechelen, Belgium). <h3>Disclosure of Interests</h3> Rohit Aggarwal Consultant of: Mallinckrodt, Octapharma, CSL Behring, Bristol Myers-Squibb, EMD Serono, Kezar, Pfizer, AstraZeneca, Alexion, Argenx, Boehringer Ingelheim, Corbus, Janssen, Kyverna, Roivant, Merck, Galapagos, Actigraph, Abbvie, Scipher, Horizontal Therapeutics, Teva, Biogen, Beigene, ANI Pharmaceutical, Nuvig, Capella, CabalettaBio, Grant/research support from: Mallinckrodt, Pfizer, Bristol Myers-Squibb, Q32, EMD Serono, Janssen, Boehringer Ingelheim, Eric F. Morand Speakers bureau: AstraZeneca, Consultant of: AbbVie, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono, UCB, Amgen, Biogen, CSL, Neovacs and Wolf Biotherapeutics, Grant/research support from: AstraZeneca, AbbVie, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono, UCB, Roland Blanque Employee of: Galapagos SASU, Kenji Shoji Employee of: Galapagos SASU, Mia Jans Employee of: Galapagos NV, Florence Marsais Employee of: Galapagos SASU, Laetitia Furio Employee of: Galapagos SASU, Maikel Colli Employee of: Galapagos NV, Stephanie Lavazais Employee of: Galapagos SASU, Celine Cottereaux Employee of: Galapagos SASU, Christelle David Employee of: Galapagos SASU, Nicolas Houvenaghel Employee of: Galapagos NV, Isabelle Parent Employee of: Galapagos SASU, Emilie Lagoutte Employee of: Galapagos SASU, An Van de Water Employee of: Galapagos NV, Laetitia Perret Employee of: Galapagos SASU, Sofia Alves Employee of: Galapagos SASU, David Amantini Employee of: Galapagos SASU, Steven van der Plas Employee of: Galapagos NV, René Galien Employee of: Galapagos SASU.